Multiple myeloma (MM) is a malignancy of B (plasma) cells which affects 13,400 new patients annually and is presently incurable. Interleukin-6 (IL-6), a differentiation factor for normal B cells, mediate growth of MM cells. However, whether MM cells or bone marrow stromal cells (BMSCs) are the source of IL-6, thereby mediating growth in an autocrine or paracrine mechanism, respectively, remains controversial. The major goal of this application is to identify the source and regulation of IL-6 production in MM. The applicant's previous studies demonstrate that MM cells specifically adhere to BMSCs,which results in upregulation of BMSC- derived IL- 6 and associated increases in DNA synthesis by IL-6 responsive MM cells. Although he has identified several ligand receptor pairs which mediate adhesion of MM cells to BMSCs (B1 and B2 integrins, CD44), he cannot yet fully account for binding and related IL-6 secretion. The applicant's preliminary studies also suggest that both MM cells and BMSCs express CD40 and the triggering with CD40 ligand (CD40L) upregulates IL-6 secretion from both MM cells and BMSCs, proliferation of MM cells, and expression of CD80 and other adhesion molecules on MM cells. Moreover, MM cells are the only B cell malignancy to express CD28, the ligand for CD80. He proposes to examine the role of CD40-CD40L and CD28-CD80 interaction in IL-6 mediated growth of MM. The applicant will focus on two model systems: his well characterized MM cell to BMSC adhesion system; and direct triggering of MM cells and BMSCs via cell surface determinants. He will define the mechanism of IL-6 induction under specific conditions (i.e., CD40: triggering) and in specific cells (i.e., MM cells, fibroblasts, etc.). He will delineate transcriptional versus post transcriptional mechanisms of IL-6 induction, and when transcription is increased, utilize IL-6 CAT reporter assays to determine which binding domain(s) on the IL-6 promoter confer responsiveness. Only under conditions where IL-6 is induced in MM cells or BMSCs, and predicated upon his CAT assay results, he will selectively characterize signalling cascades regulating IL-6. He will study IL-6 regulation in normal B cells or BMSCs only under those limited specific conditions shown to trigger IL-6 in MM cells or MM BMSCs, in order to identify differences that may be intrinsic to MM.
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